24 results on '"Carelli, V."'
Search Results
2. Leber's hereditary optic neuropathy: Biochemical effect of 11778/ND1 mutations and correlation...
- Author
-
Carelli, V. and Sangiorgi, S.
- Published
- 1997
- Full Text
- View/download PDF
3. Revisiting the issue of mitochondrial DNA content in optic mitochondriopathies.
- Author
-
Iommarini L, Maresca A, Caporali L, Valentino ML, Liguori R, Giordano C, and Carelli V
- Published
- 2012
- Full Text
- View/download PDF
4. Severe CMT type 2 with fatal encephalopathy associated with a novel MFN2 splicing mutation.
- Author
-
Boaretto F, Vettori A, Casarin A, Vazza G, Muglia M, Rossetto MG, Cavallaro T, Rizzuto N, Carelli V, Salviati L, Mostacciuolo ML, Martinuzzi A, Boaretto, F, Vettori, A, Casarin, A, Vazza, G, Muglia, M, Rossetto, M G, Cavallaro, T, and Rizzuto, N
- Published
- 2010
- Full Text
- View/download PDF
5. POLG mutations causing ophthalmoplegia, sensorimotor polyneuropathy, ataxia, and deafness.
- Author
-
Mancuso, M, Filosto, M, Bellan, M, Liguori, R, Montagna, P, Baruzzi, A, DiMauro, S, and Carelli, V
- Published
- 2004
- Full Text
- View/download PDF
6. Mitochondrial disorders
- Author
-
VALERIO CARELLI, Massimo Zeviani, Zeviani M., and Carelli V.
- Subjects
Mitochondrial Diseases ,Maternal inheritance ,Ubiquinone ,Coenzymes ,Neurodegenerative Diseases ,Genetic Therapy ,DNA ,Respiratory chain ,Mitochondrial disease ,Mitochondrial DNA ,Oxidative phosphorylation ,DNA, Mitochondrial ,Genetic Predisposition to Disease ,Humans ,Mitochondria ,Mutation ,Oxidative Phosphorylation ,Antioxidants ,Mitochondrial ,Neurology ,Cytoprotection ,Animals ,Neurology (clinical) - Abstract
Mitochondrial disorders are increasingly acknowledged as a major category in clinical neurology. In this review we highlight the most recent advances in the field, including the characterization of new disease genes, new physiopathological insights, and the role of mitochondrial dysfunction in neurodegeneration.Substantial progress has been made on the genetic basis and pathogenic mechanisms in disorders associated with altered mitochondrial DNA stability and expression. These defects include a wide spectrum of neurological conditions caused by genetic abnormalities of the mitochondrial replication and translation machineries, and of the metabolic pathways controlling the nucleotide supply to organelles, cells and tissues. Another relevant contribution has been given to the molecular dissection of coenzyme Q deficiency, a clinically heterogeneous, potentially treatable condition, thanks to the biochemical and genetic characterization of the first defects in coenzyme Q biosynthesis. Finally, the genetic determinants controlling the penetrance of mitochondrial disorders, as well as the role of mitochondrial dysfunction in neurodegenerative conditions such as Parkinson's and Huntington's diseases, have been investigated in both patients and animal models.The dual genetic contribution controlling mitochondrial biogenesis, and the intricacy and universality of the metabolic pathways operating in the mitochondrion explain the complexity of what is now known as 'mitochondrial medicine'.
- Published
- 2007
7. Recurrence of Visual Loss in Recessive Leber Hereditary Optic Neuropathy: New Paradigm.
- Author
-
Barboni P, Battista M, Brotto L, Nucci P, Checchin L, Bandello F, Fiorini C, Ormanbekova D, Carelli V, Cascavilla ML, and Caporali L
- Abstract
Competing Interests: The authors report no conflicts of interest.
- Published
- 2024
- Full Text
- View/download PDF
8. Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial.
- Author
-
Karaa A, Bertini E, Carelli V, Cohen BH, Enns GM, Falk MJ, Goldstein A, Gorman GS, Haas R, Hirano M, Klopstock T, Koenig MK, Kornblum C, Lamperti C, Lehman A, Longo N, Molnar MJ, Parikh S, Phan H, Pitceathly RDS, Saneto R, Scaglia F, Servidei S, Tarnopolsky M, Toscano A, Van Hove JLK, Vissing J, Vockley J, Finman JS, Brown DA, Shiffer JA, and Mancuso M
- Subjects
- Humans, Female, Middle Aged, Male, Merozoite Surface Protein 1 therapeutic use, Fatigue, Double-Blind Method, Treatment Outcome, Quality of Life, Mitochondrial Myopathies drug therapy
- Abstract
Background and Objectives: Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting physical function, exercise capacity, and quality of life (QoL). Current PMM standards of care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically confirmed PMM., Methods: After screening, eligible participants were randomized 1:1 to receive either 24 weeks of elamipretide at a dose of 40 mg/d or placebo subcutaneously. Primary efficacy endpoints included change from baseline to week 24 on the distance walked on the 6-minute walk test (6MWT) and total fatigue on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA). Secondary endpoints included most bothersome symptom score on the PMMSA, NeuroQoL Fatigue Short-Form scores, and the patient global impression and clinician global impression of PMM symptoms., Results: Participants (N = 218) were randomized (n = 109 elamipretide; n = 109 placebo). The m0ean age was 45.6 years (64% women; 94% White). Most of the participants (n = 162 [74%]) had mitochondrial DNA (mtDNA) alteration, with the remainder having nuclear DNA (nDNA) defects. At screening, the most frequent bothersome PMM symptom on the PMMSA was tiredness during activities (28.9%). At baseline, the mean distance walked on the 6MWT was 336.7 ± 81.2 meters, the mean score for total fatigue on the PMMSA was 10.6 ± 2.5, and the mean T score for the Neuro-QoL Fatigue Short-Form was 54.7 ± 7.5. The study did not meet its primary endpoints assessing changes in the 6MWT and PMMSA total fatigue score (TFS). Between the participants receiving elamipretide and those receiving placebo, the difference in the least squares mean (SE) from baseline to week 24 on distance walked on the 6MWT was -3.2 (95% CI -18.7 to 12.3; p = 0.69) meters, and on the PMMSA, the total fatigue score was -0.07 (95% CI -0.10 to 0.26; p = 0.37). Elamipretide treatment was well-tolerated with most adverse events being mild to moderate in severity., Discussion: Subcutaneous elamipretide treatment did not improve outcomes in the 6MWT and PMMSA TFS in patients with PMM. However, this phase-3 study demonstrated that subcutaneous elamipretide is well-tolerated., Trial Registration Information: Trial registered with clinicaltrials.gov, Clinical Trials Identifier: NCT03323749; submitted on October 12, 2017; first patient enrolled October 9, 2017., Clinicaltrials: gov/ct2/show/NCT03323749?term = elamipretide&draw = 2&rank = 9., Classification of Evidence: This study provides Class I evidence that elamipretide does not improve the 6MWT or fatigue at 24 weeks compared with placebo in patients with primary mitochondrial myopathy., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
- Published
- 2023
- Full Text
- View/download PDF
9. Gene Therapies for the Treatment of Leber Hereditary Optic Neuropathy.
- Author
-
Sahel JA, Newman NJ, Yu-Wai-Man P, Vignal-Clermont C, Carelli V, Biousse V, Moster ML, Sergott R, Klopstock T, Sadun AA, Blouin L, Katz B, and Taiel M
- Subjects
- Genetic Therapy, Humans, Optic Atrophy, Hereditary, Leber genetics, Optic Atrophy, Hereditary, Leber therapy
- Published
- 2021
- Full Text
- View/download PDF
10. Combined Optic Atrophy and Rod-Cone Dystrophy Expands the RTN4IP1 (Optic Atrophy 10) Phenotype.
- Author
-
Rajabian F, Manitto MP, Palombo F, Caporali L, Grazioli A, Starace V, Arrigo A, Cascavilla ML, La Morgia C, Barboni P, Bandello F, Carelli V, and Battaglia Parodi M
- Subjects
- Adult, Carrier Proteins metabolism, Cone-Rod Dystrophies diagnosis, Cone-Rod Dystrophies metabolism, Female, Follow-Up Studies, Humans, Mitochondrial Proteins metabolism, Optic Atrophy diagnosis, Optic Atrophy metabolism, Phenotype, Time Factors, Tomography, Optical Coherence methods, Visual Fields physiology, Carrier Proteins genetics, Cone-Rod Dystrophies genetics, Mitochondrial Proteins genetics, Mutation, Optic Atrophy genetics, Retinal Ganglion Cells pathology, Rod Cell Outer Segment pathology
- Abstract
Competing Interests: The authors report no conflicts of interest.
- Published
- 2021
- Full Text
- View/download PDF
11. Long-Term Follow-Up After Unilateral Intravitreal Gene Therapy for Leber Hereditary Optic Neuropathy: The RESTORE Study.
- Author
-
Biousse V, Newman NJ, Yu-Wai-Man P, Carelli V, Moster ML, Vignal-Clermont C, Klopstock T, Sadun AA, Sergott RC, Hage R, Esposti S, La Morgia C, Priglinger C, Karanja R, Blouin L, Taiel M, and Sahel JA
- Subjects
- Adolescent, Adult, Aged, DNA, Mitochondrial genetics, Double-Blind Method, Female, Follow-Up Studies, Humans, Intravitreal Injections, Male, Middle Aged, Mutation, NADH Dehydrogenase genetics, NADH Dehydrogenase metabolism, Optic Atrophy, Hereditary, Leber genetics, Optic Atrophy, Hereditary, Leber physiopathology, Quality of Life, Time Factors, Tomography, Optical Coherence, Young Adult, Genetic Therapy methods, Optic Atrophy, Hereditary, Leber therapy, Recombinant Proteins administration & dosage, Visual Acuity, Visual Fields
- Abstract
Background: RESCUE and REVERSE were 2 Phase 3 clinical trials that assessed the efficacy and safety of intravitreal gene therapy with lenadogene nolparvovec (rAAV2/2-ND4) for the treatment of Leber hereditary optic neuropathy (LHON). RESTORE is the long-term follow-up study of subjects treated in the RESCUE and REVERSE trials., Methods: In RESCUE and REVERSE, 76 subjects with LHON because of the m.11778 G>A mutation in the mitochondrial gene ND4 received a single unilateral intravitreal injection of lenadogene nolparvovec. After 96 weeks, 61 subjects were enrolled in the long-term follow-up study RESTORE. The best-corrected visual acuity (BCVA) was assessed over a period of up to 52 months after onset of vision loss. A locally estimated scatterplot smoothing regression model was used to analyze changes in BCVA over time. Vision-related quality of life was reported using the visual function questionnaire-25 (VFQ-25)., Results: The population of MT-ND4 subjects enrolled in RESTORE was representative of the combined cohorts of RESCUE and REVERSE for mean age (35.1 years) and gender distribution (79% males). There was a progressive and sustained improvement of BCVA up to 52 months after the onset of vision loss. The final mean BCVA was 1.26 logarithm of the minimal angle of resolution 48 months after the onset of vision loss. The mean VFQ-25 composite score increased by 7 points compared with baseline., Conclusion: The treatment effect of lenadogene nolparvovec on BCVA and vision-related quality of life observed 96 weeks (2 years) after treatment in RESCUE and REVERSE was sustained at 3 years in RESTORE, with a maximum follow-up of 52 months (4.3 years) after the onset of vision loss., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the North American Neuro-Opthalmology Society.)
- Published
- 2021
- Full Text
- View/download PDF
12. Cross-Sectional Analysis of Baseline Visual Parameters in Subjects Recruited Into the RESCUE and REVERSE ND4-LHON Gene Therapy Studies.
- Author
-
Moster ML, Sergott RC, Newman NJ, Yu-Wai-Man P, Carelli V, Bryan MS, Smits G, Biousse V, Vignal-Clermont C, Klopstock T, Sadun AA, DeBusk AA, Carbonelli M, Hage R, Priglinger S, Karanjia R, Blouin L, Taiel M, Katz B, and Sahel JA
- Subjects
- Adolescent, Adult, Aged, Cross-Sectional Studies, DNA, Mitochondrial genetics, Double-Blind Method, Female, Humans, Male, Middle Aged, Optic Atrophy, Hereditary, Leber genetics, Optic Atrophy, Hereditary, Leber therapy, Retinal Ganglion Cells pathology, Tomography, Optical Coherence methods, Young Adult, Genetic Therapy methods, Optic Atrophy, Hereditary, Leber physiopathology, Visual Acuity, Visual Fields physiology
- Abstract
Objective: This report presents a cross-sectional analysis of the baseline characteristics of subjects with Leber hereditary optic neuropathy enrolled in the gene therapy trials RESCUE and REVERSE, to illustrate the evolution of visual parameters over the first year after vision loss., Methods: RESCUE and REVERSE were 2 phase III clinical trials designed to assess the efficacy of rAAV2/2-ND4 gene therapy in ND4-LHON subjects. At enrollment, subjects had vision loss for ≤6 months in RESCUE, and between 6 and 12 months in REVERSE. Functional visual parameters (best-corrected visual acuity [BCVA], contrast sensitivity [CS], and Humphrey Visual Field [HVF]) and structural parameters assessed by spectral-domain optical coherence tomography were analyzed in both cohorts before treatment. The cross-sectional analysis of functional and anatomic parameters included the baseline values collected in all eyes at 2 different visits (Screening and Inclusion)., Results: Seventy-six subjects were included in total, 39 in RESCUE and 37 in REVERSE. Mean BCVA was significantly worse in RESCUE subjects compared with REVERSE subjects (1.29 and 1.61 LogMAR respectively, P = 0.0029). Similarly, mean CS and HVF were significantly more impaired in REVERSE vs RESCUE subjects (P < 0.005). The cross-sectional analysis showed that the monthly decrease in BCVA, ganglion cell layer macular volume, and retinal nerve fiber layer thickness was much more pronounced in the first 6 months after onset (+0.24 LogMAR, -0.06 mm3, and -6.00 μm respectively) than between 6 and 12 months after onset (+0.02 LogMAR, -0.01 mm3, and -0.43 μm respectively)., Conclusion: LHON progresses rapidly in the first months following onset during the subacute phase, followed by relative stabilization during the dynamic phase., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the North American Neuro-Opthalmology Society.)
- Published
- 2021
- Full Text
- View/download PDF
13. Visual Outcomes in Leber Hereditary Optic Neuropathy Patients With the m.11778G>A (MTND4) Mitochondrial DNA Mutation.
- Author
-
Newman NJ, Carelli V, Taiel M, and Yu-Wai-Man P
- Subjects
- DNA Mutational Analysis, Humans, NADH Dehydrogenase metabolism, Optic Atrophy, Hereditary, Leber metabolism, Optic Atrophy, Hereditary, Leber physiopathology, DNA, Mitochondrial genetics, NADH Dehydrogenase genetics, Optic Atrophy, Hereditary, Leber genetics, Point Mutation, Visual Acuity
- Abstract
Background: Leber hereditary optic neuropathy (LHON) is a maternally inherited bilaterally blinding optic neuropathy, predominantly affecting otherwise healthy young individuals, mostly men. The visual prognosis is generally poor, with most patients worsening to at least 20/200 visual acuity. The m.11778G>A (MTND4) mitochondrial DNA mutation is the most common cause of LHON and is associated with poor outcomes and limited potential for meaningful visual recovery. Treatments for LHON are limited, and clinical trials are hampered by inadequate data regarding the natural history of visual loss and recovery. In this article, we review the current literature specifically related to visual function of LHON patients with the m.11778G>A mutation., Evidence Acquisition: Literature review was performed using MEDLINE through PubMed, Cochrane Reviews Library, and Orpha.net with search terms of "Leber hereditary optic neuropathy," "LHON," "ND4," "G11778A," "visual acuity," "nadir," "natural history," and "registry." All English-language, peer-reviewed publications with study cohorts of at least 5 LHON patients with the molecularly confirmed m.11778G>A mutation were included., Results: Meta-analysis of 12 retrospective and 3 prospective studies provided visual function information on 695 LHON patients with the m.11778G>A mutation, 100 (14.4%) of whom were reported to have "recovered" some vision, although definitions of "recovery" varied among studies and idebenone use could not always be excluded. When incorporating age at onset of visual loss into the analyses, and specifically addressing those patients aged 15 years or older, meaningful visual recovery occurred in 23 of 204 (11.3%) patients. A younger age at onset, especially less than 12 years, portends a better visual prognosis and a different natural history of visual loss progression and recovery than in adults., Conclusions: The classic presentation of LHON patients with the m.11778G>A mutation of severe visual loss with rare or poor recovery from nadir still holds true for most affected individuals. Among patients 15 years and older, recovery of meaningful vision likely occurs in less than 20% of patients, irrespective of how recovery is defined, and ultimate visual acuities of better than 20/200 are rare. Adequate prospective studies with sufficient sample sizes of genotypically homogeneous untreated LHON patients stratified by age, immediately enrolled when symptomatic, followed regularly for adequate periods of time with consistent measures of visual function, and analyzed with a standard definition of visual improvement are unfortunately lacking. Future clinical trials for LHON will require more standardized reporting of the natural history of this disorder.
- Published
- 2020
- Full Text
- View/download PDF
14. Exploring metabolic reprogramming in melanoma via acquired resistance to the oxidative phosphorylation inhibitor phenformin.
- Author
-
Pistoni M, Tondelli G, Gallo C, Torricelli F, Maresca A, Carelli V, Ciarrocchi A, and Dallaglio K
- Subjects
- Humans, Hypoglycemic Agents pharmacology, Phenformin pharmacology, Cellular Reprogramming immunology, Hypoglycemic Agents therapeutic use, Melanoma genetics, Phenformin therapeutic use
- Abstract
Therapeutic failures in cancer therapy are often associated with metabolic plasticity. The use of metabolic modulators as anti-cancer agents has been effective in correcting metabolic alterations; however, molecular events behind metabolic switch are still largely unexplored. Herein, we characterize the molecular and functional events that follow prolonged oxidative phosphorylation inhibition by phenformin in order to study how melanoma cells adapt to this specific metabolic pressure. We show that melanoma cells cultured up to 3 months with high doses of phenformin (R-cells) are less viable and migrate and invade less than parental (S-) cells. Microarray analysis of R-melanoma cells reveals a switch in the energy production strategy accompanied by the modulation of several immunological-associated genes. R-cells display low oxygen consumption rate and high basal extracellular acidification rate. When treated with vemurafenib, R-cell viability, growth and extracellular signal-regulated kinase activation decrease. Finally, phenformin withdrawal reverts R-cells phenotype. In summary, our study provides an in vitro model of on-off metabolic switch in melanoma and reveals interesting molecular signatures controlling metabolic reprogramming in this tumour.
- Published
- 2020
- Full Text
- View/download PDF
15. International Consensus Statement on the Clinical and Therapeutic Management of Leber Hereditary Optic Neuropathy.
- Author
-
Carelli V, Carbonelli M, de Coo IF, Kawasaki A, Klopstock T, Lagrèze WA, La Morgia C, Newman NJ, Orssaud C, Pott JWR, Sadun AA, van Everdingen J, Vignal-Clermont C, Votruba M, Yu-Wai-Man P, and Barboni P
- Subjects
- Antioxidants therapeutic use, Congresses as Topic, Humans, International Cooperation, Ubiquinone therapeutic use, Consensus, Disease Management, Ophthalmology, Optic Atrophy, Hereditary, Leber drug therapy, Societies, Medical, Ubiquinone analogs & derivatives
- Abstract
Leber hereditary optic neuropathy (LHON) is currently estimated as the most frequent mitochondrial disease (1 in 27,000-45,000). Its molecular pathogenesis and natural history is now fairly well understood. LHON also is the first mitochondrial disease for which a treatment has been approved (idebenone-Raxone, Santhera Pharmaceuticals) by the European Medicine Agency, under exceptional circumstances because of the rarity and severity of the disease. However, what remains unclear includes the optimal target population, timing, dose, and frequency of administration of idebenone in LHON due to lack of accepted definitions, criteria, and general guidelines for the clinical management of LHON. To address these issues, a consensus conference with a panel of experts from Europe and North America was held in Milan, Italy, in 2016. The intent was to provide expert consensus statements for the clinical and therapeutic management of LHON based on the currently available evidence. We report the conclusions of this conference, providing the guidelines for clinical and therapeutic management of LHON.
- Published
- 2017
- Full Text
- View/download PDF
16. Reactive Oxygen Species in Mitochondrial Optic Neuropathies: Comment.
- Author
-
Sadun AA, Karanjia R, Pan BX, Ross-Cisneros FN, and Carelli V
- Subjects
- Humans, Optic Chiasm metabolism, Optic Nerve Diseases complications, Scotoma complications, Superoxides metabolism
- Published
- 2015
- Full Text
- View/download PDF
17. Phenotypic heterogeneity of the 8344A>G mtDNA "MERRF" mutation.
- Author
-
Mancuso M, Orsucci D, Angelini C, Bertini E, Carelli V, Comi GP, Minetti C, Moggio M, Mongini T, Servidei S, Tonin P, Toscano A, Uziel G, Bruno C, Caldarazzo Ienco E, Filosto M, Lamperti C, Martinelli D, Moroni I, Musumeci O, Pegoraro E, Ronchi D, Santorelli FM, Sauchelli D, Scarpelli M, Sciacco M, Spinazzi M, Valentino ML, Vercelli L, Zeviani M, and Siciliano G
- Subjects
- Adult, Age of Onset, Databases, Genetic, Disease Progression, Female, Humans, MERRF Syndrome pathology, Magnetic Resonance Imaging, Male, Middle Aged, Retrospective Studies, DNA, Mitochondrial genetics, MERRF Syndrome genetics, MERRF Syndrome physiopathology, Mutation genetics, Phenotype
- Abstract
Objectives: Myoclonic epilepsy with ragged-red fibers (MERRF) is a rare mitochondrial syndrome, mostly caused by the 8344A>G mitochondrial DNA mutation. Most of the previous studies have been based on single case/family reports or series with few patients. The primary aim of this study was the characterization of a large cohort of patients with the 8344A>G mutation. The secondary aim was revision of the previously published data., Methods: Retrospective, database-based study (Nation-wide Italian Collaborative Network of Mitochondrial Diseases) and systematic revision., Results: Forty-two patients carrying the mutation were identified. The great majority did not have full-blown MERRF syndrome. Myoclonus was present in 1 of 5 patients, whereas myopathic signs and symptoms, generalized seizures, hearing loss, eyelid ptosis, and multiple lipomatosis represented the most common clinical features. Some asymptomatic mutation carriers have also been observed. Myoclonus was more strictly associated with ataxia than generalized seizures in adult 8344A>G subjects. Considering all of the 321 patients so far available, including our dataset and previously published cases, at the mean age of approximately 35 years, the clinical picture was characterized by the following signs/symptoms, in descending order: myoclonus, muscle weakness, ataxia (35%-45% of patients); generalized seizures, hearing loss (25%-34.9%); cognitive impairment, multiple lipomatosis, neuropathy, exercise intolerance (15%-24.9%); and increased creatine kinase levels, ptosis/ophthalmoparesis, optic atrophy, cardiomyopathy, muscle wasting, respiratory impairment, diabetes, muscle pain, tremor, migraine (5%-14.9%)., Conclusions: Our results showed higher clinical heterogeneity than commonly thought. Moreover, MERRF could be better defined as a myoclonic ataxia rather than a myoclonic epilepsy.
- Published
- 2013
- Full Text
- View/download PDF
18. Axonal degeneration in peripheral nerves in a case of Leber hereditary optic neuropathy.
- Author
-
Mnatsakanyan L, Ross-Cisneros FN, Carelli V, Wang MY, and Sadun AA
- Subjects
- Aged, Brachial Plexus Neuropathies physiopathology, Disease Progression, Female, Humans, Optic Atrophy, Hereditary, Leber physiopathology, Peripheral Nervous System Diseases physiopathology, Wallerian Degeneration genetics, Wallerian Degeneration pathology, Wallerian Degeneration physiopathology, Brachial Plexus Neuropathies genetics, Brachial Plexus Neuropathies pathology, Optic Atrophy, Hereditary, Leber complications, Optic Atrophy, Hereditary, Leber genetics, Peripheral Nervous System Diseases genetics, Peripheral Nervous System Diseases pathology
- Abstract
Background: Leber hereditary optic neuropathy (LHON) is a mitochondrial DNA (mtDNA) genetic disorder characterized by profound bilateral loss of central vision due to selective loss of retinal ganglion cells. Most patients with LHON do not have complaints related to the peripheral nervous system. We investigated possible qualitative and quantitative histological changes in the peripheral nerve of a patient with LHON as compared to normal controls., Methods: Brachial plexus specimens were obtained at necropsy from a patient with LHON carrying the 3460/ND1 mtDNA mutation and age-matched controls without known history of neurological disease. The nerves were evaluated by light microscope coupled to a digital camera-based morphometric analysis and electron microscopy., Results: Extensive axonal degeneration of the large heavily myelinated fibers was found in the brachial plexus from the patient with LHON. In LHON nerve fascicles, we counted over 10 times as many degenerated profiles as found in the control nerve fascicles., Conclusions: Microscopic examination of the brachial plexus in the patient with LHON clearly demonstrated a significant pattern of neurodegeneration. Our study suggests that peripheral neuropathy may be a subclinical feature associated with LHON.
- Published
- 2011
- Full Text
- View/download PDF
19. Myelin, mitochondria, and autoimmunity: what's the connection?
- Author
-
Carelli V and Bellan M
- Subjects
- Autoimmunity genetics, Energy Metabolism genetics, Genetic Predisposition to Disease genetics, Humans, Mitochondria genetics, Mitochondria metabolism, Myelin Sheath genetics, Myelin Sheath metabolism, Nerve Fibers, Myelinated immunology, Nerve Fibers, Myelinated metabolism, Nerve Fibers, Myelinated pathology, Optic Atrophy, Autosomal Dominant metabolism, Optic Atrophy, Hereditary, Leber genetics, Optic Atrophy, Hereditary, Leber metabolism, Optic Nerve immunology, Optic Nerve metabolism, Optic Nerve physiopathology, Phenotype, Autoimmunity immunology, Mitochondria immunology, Myelin Sheath immunology, Optic Atrophy, Autosomal Dominant genetics, Optic Atrophy, Autosomal Dominant immunology, Optic Atrophy, Hereditary, Leber immunology
- Published
- 2008
- Full Text
- View/download PDF
20. Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus.
- Author
-
La Morgia C, Achilli A, Iommarini L, Barboni P, Pala M, Olivieri A, Zanna C, Vidoni S, Tonon C, Lodi R, Vetrugno R, Mostacci B, Liguori R, Carroccia R, Montagna P, Rugolo M, Torroni A, and Carelli V
- Subjects
- Adenosine Triphosphate deficiency, Adult, DNA Mutational Analysis, Electroencephalography, Electromyography, Female, Gene Frequency, Genetic Testing, Genotype, Humans, Inheritance Patterns genetics, Magnetic Resonance Spectroscopy, Male, Middle Aged, Mitochondria genetics, Mitochondria metabolism, Mitochondria pathology, Myoclonus physiopathology, Optic Atrophy, Hereditary, Leber complications, Optic Atrophy, Hereditary, Leber physiopathology, Pedigree, Recurrence, DNA, Mitochondrial genetics, Energy Metabolism genetics, Genetic Predisposition to Disease genetics, Mutation genetics, Myoclonus genetics, Optic Atrophy, Hereditary, Leber genetics
- Abstract
Objective: To investigate the mechanisms underlying myoclonus in Leber hereditary optic neuropathy (LHON)., Methods: Five patients and one unaffected carrier from two Italian families bearing the homoplasmic 11778/ND4 and 3460/ND1 mutations underwent a uniform investigation including neurophysiologic studies, muscle biopsy, serum lactic acid after exercise, and muscle ((31)P) and cerebral ((1)H) magnetic resonance spectroscopy (MRS). Biochemical investigations on fibroblasts and complete mitochondrial DNA (mtDNA) sequences of both families were also performed., Results: All six individuals had myoclonus. In spite of a normal EEG background and the absence of giant SEPs and C reflex, EEG-EMG back-averaging showed a preceding jerk-locked EEG potential, consistent with a cortical generator of the myoclonus. Specific comorbidities in the 11778/ND4 family included muscular cramps and psychiatric disorders, whereas features common to both families were migraine and cardiologic abnormalities. Signs of mitochondrial proliferation were seen in muscle biopsies and lactic acid elevation was observed in four of six patients. (31)P-MRS was abnormal in five of six patients and (1)H-MRS showed ventricular accumulation of lactic acid in three of six patients. Fibroblast ATP depletion was evident at 48 hours incubation with galactose in LHON/myoclonus patients. Sequence analysis revealed haplogroup T2 (11778/ND4 family) and U4a (3460/ND1 family) mtDNAs. A functional role for the non-synonymous 4136A>G/ND1, 9139G>A/ATPase6, and 15773G>A/cyt b variants was supported by amino acid conservation analysis., Conclusions: Myoclonus and other comorbidities characterized our Leber hereditary optic neuropathy (LHON) families. Functional investigations disclosed a bioenergetic impairment in all individuals. Our sequence analysis suggests that the LHON plus phenotype in our cases may relate to the synergic role of mtDNA variants.
- Published
- 2008
- Full Text
- View/download PDF
21. Mitochondrial disorders.
- Author
-
Zeviani M and Carelli V
- Subjects
- Humans, Mitochondria metabolism, Mitochondrial Diseases metabolism, Mitochondrial Diseases physiopathology, Mutation genetics, Neurodegenerative Diseases genetics, Neurodegenerative Diseases metabolism, Neurodegenerative Diseases physiopathology, Ubiquinone deficiency, DNA, Mitochondrial genetics, Genetic Predisposition to Disease genetics, Mitochondria genetics, Mitochondrial Diseases genetics, Oxidative Phosphorylation
- Abstract
Purpose of Review: Mitochondrial disorders are increasingly acknowledged as a major category in clinical neurology. In this review we highlight the most recent advances in the field, including the characterization of new disease genes, new physiopathological insights, and the role of mitochondrial dysfunction in neurodegeneration., Recent Findings: Substantial progress has been made on the genetic basis and pathogenic mechanisms in disorders associated with altered mitochondrial DNA stability and expression. These defects include a wide spectrum of neurological conditions caused by genetic abnormalities of the mitochondrial replication and translation machineries, and of the metabolic pathways controlling the nucleotide supply to organelles, cells and tissues. Another relevant contribution has been given to the molecular dissection of coenzyme Q deficiency, a clinically heterogeneous, potentially treatable condition, thanks to the biochemical and genetic characterization of the first defects in coenzyme Q biosynthesis. Finally, the genetic determinants controlling the penetrance of mitochondrial disorders, as well as the role of mitochondrial dysfunction in neurodegenerative conditions such as Parkinson's and Huntington's diseases, have been investigated in both patients and animal models., Summary: The dual genetic contribution controlling mitochondrial biogenesis, and the intricacy and universality of the metabolic pathways operating in the mitochondrion explain the complexity of what is now known as 'mitochondrial medicine'.
- Published
- 2007
- Full Text
- View/download PDF
22. Leber hereditary optic neuropathy possibly triggered by exposure to tire fire.
- Author
-
Sanchez RN, Smith AJ, Carelli V, Sadun AA, and Keltner JL
- Subjects
- Adult, Carbon adverse effects, Child, Child, Preschool, DNA Mutational Analysis, Female, Genetic Predisposition to Disease genetics, Humans, Male, Mutation genetics, Optic Atrophy, Hereditary, Leber diagnosis, Optic Atrophy, Hereditary, Leber physiopathology, Optic Nerve pathology, Optic Nerve physiopathology, Pedigree, Petroleum adverse effects, Rubber adverse effects, Air Pollutants adverse effects, DNA, Mitochondrial genetics, Optic Atrophy, Hereditary, Leber etiology
- Abstract
We report three members of one family, a mother and two daughters aged 4 and 7 years, who developed visual loss from Leber hereditary optic neuropathy within a 19-month period. All three had been exposed to smoke from two large rubber tire fires within the previous 24 months, suggesting the possibility of an epigenetic triggering factor.
- Published
- 2006
- Full Text
- View/download PDF
23. Mitochondrial disorders.
- Author
-
Zeviani M and Carelli V
- Subjects
- Animals, Antioxidants metabolism, Coenzymes, Cytoprotection, DNA, Mitochondrial genetics, Humans, Mitochondria genetics, Mitochondria pathology, Mitochondrial Diseases classification, Oxidative Phosphorylation, Ubiquinone deficiency, Genetic Therapy, Mitochondrial Diseases genetics, Mitochondrial Diseases therapy, Mutation, Ubiquinone analogs & derivatives
- Abstract
Purpose of Review: We present here a review of the most recent and relevant contributions on the genetic, biochemical and clinical aspects of mitochondrial biogenesis and disease. The field of mitochondrial medicine is evolving fast. After more than 10 years of investigation into mitochondrial DNA defects, a new impulse is now due to progress in three main areas of research., Recent Findings: Some of the basic notions on mitochondrial genetics are being challenged by new data on fundamental biological functions such as mitochondrial DNA replication, transcription and the nuclear control of mitochondrial DNA variations, with important implications in the understanding of the molecular mechanisms of disease. The rapidly increasing identification of nuclear genes responsible for oxidative phosphorylation-related disorders, has greatly broadened the concept of mitochondrial disease., Summary: The development of animal models and the use of multiple strategies are all accelerating our understanding of the pathogenesis in mitochondrial disorders, by integrating in-vivo, in-vitro and in-silico approaches. Finally, some interesting progress has recently been made on gene therapy, giving hope for the future treatment of these conditions.
- Published
- 2003
- Full Text
- View/download PDF
24. Leber's hereditary optic neuropathy: biochemical effect of 11778/ND4 and 3460/ND1 mutations and correlation with the mitochondrial genotype.
- Author
-
Carelli V, Ghelli A, Ratta M, Bacchilega E, Sangiorgi S, Mancini R, Leuzzi V, Cortelli P, Montagna P, Lugaresi E, and Degli Esposti M
- Subjects
- Antineoplastic Agents, Phytogenic pharmacology, Blood Platelets chemistry, Blood Platelets ultrastructure, Family Health, Female, Furans pharmacology, Genotype, Humans, Leukocytes chemistry, Leukocytes ultrastructure, Male, Mitochondria drug effects, Mitochondria enzymology, Mitochondria genetics, NADH, NADPH Oxidoreductases metabolism, Optic Atrophies, Hereditary enzymology, Pedigree, Phenotype, Rotenone pharmacology, DNA, Mitochondrial analysis, Optic Atrophies, Hereditary genetics, Point Mutation
- Abstract
To clarify the bioenergetic relevance of mtDNA mutations in Leber's hereditary optic neuropathy (LHON), we investigated affected individuals and healthy carriers from six Italian LHON families harboring the 11778/ND4 and the 3460/ND1 mtDNA mutations. The enzymatic activities of mitochondrial complex I and its sensitivity to the potent inhibitors rotenone and rolliniastatin-2 were studied in mitochondrial particles from platelets, in correlation with mtDNA analysis of platelets and leukocytes. In platelets homoplasmic for mutant mtDNA, both 11778/ND4 and 3460/ND1 mutations induced resistance to rotenone and the 3460/ND1 mutation also provoked a marked decrease in the specific activity of complex I. Individuals heteroplasmic in platelets for either mutation showed normal biochemical features, indicating functional complementation of wild-type mtDNA. There was no correlation between the clinical status and mtDNA homo/heteroplasmy in platelets, but the biochemical features correlated with the mitochondrial genotype of platelets. In some cases, the degree of mtDNA heteroplasmy differed in platelets and leukocytes from the same individual with a prevalence of wild-type mtDNA in the platelets. These results imply that biochemical studies on mitochondrial diseases should always be integrated with mtDNA analysis of the same tissue investigated and also suggest that the mtDNA analysis on the leukocyte fraction, as usually performed in LHON, does not necessarily reflect the mutant genotype level of other tissues. The differential tissue heteroplasmy may be more relevant than previously thought in determining disease penetrance.
- Published
- 1997
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.